Alkylphospholipids are Signal Transduction Modulators with Potential for Anticancer Therapy

Background:Alkylphospholipids (APLs) are synthetically derived from cell membrane components, which they target and thus modify cellular signalling and cause diverse effects. This study reviews the mechanism of action of anticancer, antiprotozoal, antibacterial and antiviral activities of ALPs, as well as their clinical use.Methods:A literature search was used as the basis of this review.Results:ALPs target lipid rafts and alter phospholipase D and C signalling cascades, which in turn will modulate the PI3K/Akt/mTOR and RAS/RAF/MEK/ERK pathways. By feedback coupling, the SAPK/JNK signalling chain is also affected. These changes lead to a G2/M phase cell cycle arrest and subsequently induce programmed cell death. The available knowledge on inhibition of AKT phosphorylation, mTOR phosphorylation and Raf down-regulation renders ALPs as attractive candidates for modern medical treatment, which is based on individualized diagnosis and therapy. Corresponding to their unusual profile of activities, their side effects result from cholinomimetic activity mainly and focus on the gastrointestinal tract. These aspects together with their bone marrow sparing features render APCs well suited for modern combination therapy. Although the clinical success has been limited in cancer diseases so far, the use of miltefosine against leishmaniosis is leading the way to better understanding their optimized use.Conclusion:Recent synthetic programs generate congeners with the increased therapeutic ratio, liposomal formulations, as well as diapeutic (or theranostic) derivatives with optimized properties. It is anticipated that these innovative modifications will pave the way for the further successful development of ALPs.

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The Antiproliferative Activity of Oxypeucedanin via Induction of G2/M Phase Cell Cycle Arrest and p53-Dependent MDM2/p21 Expression in Human Hepatoma Cells

Molecules ◽

10.3390/molecules25030501 ◽

2020 ◽

Vol 25 (3) ◽

pp. 501

Author(s):

So Hyun Park ◽

Ji-Young Hong ◽

Hyen Joo Park ◽

Sang Kook Lee

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Antiproliferative Activity ◽

Hepatoma Cells ◽

Phase Cell ◽

Human Hepatoma Cells ◽

Cycle Arrest ◽

Growth Inhibitory Activity ◽

M Phase

Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated the antiproliferative effect of OPD in SK-Hep-1 human hepatoma cells. OPD effectively inhibited the growth of SK-Hep-1 cells. Flow cytometric analysis revealed that OPD was able to induce G2/M phase cell cycle arrest in cells. The G2/M phase cell cycle arrest by OPD was associated with the downregulation of the checkpoint proteins cyclin B1, cyclin E, cdc2, and cdc25c, and the up-regulation of p-chk1 (Ser345) expression. The growth-inhibitory activity of OPD against hepatoma cells was found to be p53-dependent. The p53-expressing cells (SK-Hep-1 and HepG2) were sensitive, but p53-null cells (Hep3B) were insensitive to the antiproliferative activity of OPD. OPD also activated the expression of p53, and thus leading to the induction of MDM2 and p21, which indicates that the antiproliferative activity of OPD is in part correlated with the modulation of p53 in cancer cells. In addition, the combination of OPD with gemcitabine showed synergistic growth-inhibitory activity in SK-Hep-1 cells. These findings suggest that the anti-proliferative activity of OPD may be highly associated with the induction of G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis in SK-HEP-1 hepatoma cells.

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N-(3'-acetyl-8-nitro-2,3-dihydro-1H,3'H-spiro[quinoline-4,2'-[1,3,4]thiadiazol]-5'-yl) acetamides Induced Cell death in MCF-7 cells via G2/M Phase Cell Cycle Arrest

New Journal of Chemistry ◽

10.1039/d1nj02550c ◽

2022 ◽

Author(s):

Selvaraj Shyamsivappan ◽

Raju Vivek ◽

Thangaraj Suresh ◽

Palanivel Naveen ◽

Kaviyarasu Adhigaman ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Cycle Arrest ◽

Spectroscopic Studies ◽

Phase Cell ◽

X Ray ◽

Cycle Arrest ◽

M Phase ◽

Mcf 7

A progression of new N-(3'-acetyl-8-nitro-2,3-dihydro-1H,3'H-spiro[quinoline-4,2'-[1,3,4]thiadiazol]-5'-yl) acetamide derivatives were synthesized from potent 8-nitro quinoline-thiosemicarbazones. The synthesized compounds were characterized by different spectroscopic studies and single X-ray crystallographic studies. The compounds were...

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Novel Thiadiazoline Spiro Quinoline Analogues Induced Cell death in MCF-7 cells via G2/M Phase Cell Cycle Arrest

10.21203/rs.3.rs-289802/v1 ◽

2021 ◽

Author(s):

Selvaraj Shyamsivappan ◽

Raju Vivek ◽

Thangaraj Suresh ◽

Adhigaman Kaviyarasu ◽

Sundarasamy Amsaveni ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Cycle Arrest ◽

Spectroscopic Studies ◽

Phase Cell ◽

Quinoline Derivatives ◽

Cycle Arrest ◽

M Phase ◽

Mcf 7

Abstract A progression of novel thiadiazoline spiro quinoline derivatives were synthesized from potent thiadiazoline spiro quinoline derivatives . The synthesized compounds portrayed by different spectroscopic studies and single X-ray crystallographic studies. The compounds were assessed for in vitro anticancer properties towards MCF-7 and HeLa cells. The compounds showed superior inhibition action MCF-7 malignant growth cells. Amongst, the compound 4a showed significant inhibition activity, the cell death mechanism was evaluated by fluorescent staining, and flow cytometry, RT-PCR, and western blot analyses. The in vitro anticancer results revealed that the compound 4a induced apoptosis by inhibition of estrogen receptor alpha (ERα) and G2/M phase cell cycle arrest. The binding affinity of the compounds with ERα and pharmacokinetic properties were confirmed by molecular docking studies.

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Ferruginol exhibits anticancer effects in OVCAR-3 human ovary cancer cells by inducing apoptosis, inhibition of cancer cell migration and G2/M phase cell cycle arrest

Molecular Medicine Reports ◽

10.3892/mmr.2017.7484 ◽

2017 ◽

Vol 16 (5) ◽

pp. 7013-7017 ◽

Cited By ~ 7

Author(s):

Wen-Dong Xiong ◽

Jian Gong ◽

Chao Xing

Keyword(s):

Cell Cycle ◽

Cell Migration ◽

Cancer Cells ◽

Phase Cell ◽

Cancer Cell Migration ◽

Human Ovary ◽

Cycle Arrest ◽

Anticancer Effects ◽

Apoptosis Inhibition ◽

M Phase

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Abstract 3817: Nitric oxide-donating aspirin induces G2/M phase cell cycle arrest in human cancer cells by regulating phase transition proteins

10.1158/1538-7445.am2012-3817 ◽

2012 ◽

Author(s):

Li Gao ◽

Jennie L. Williams

Keyword(s):

Nitric Oxide ◽

Phase Transition ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Human Cancer ◽

Phase Cell ◽

Human Cancer Cells ◽

Cycle Arrest ◽

M Phase

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Abstract 574: α-santalol induces caspase-dependent apoptosis and G2/M phase cell cycle arrest in human breast cancer cells

10.1158/1538-7445.am2012-574 ◽

2012 ◽

Author(s):

Sreevidya Santha ◽

Ajay Bommareddy ◽

Brittny Rule ◽

Ruth Guillermo ◽

Radhey S. Kaushik ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Phase Cell ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Cycle Arrest ◽

M Phase

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Achillin Increases Chemosensitivity to Paclitaxel, Overcoming Resistance and Enhancing Apoptosis in Human Hepatocellular Carcinoma Cell Line Resistant to Paclitaxel (Hep3B/PTX)

Pharmaceutics ◽

10.3390/pharmaceutics11100512 ◽

2019 ◽

Vol 11 (10) ◽

pp. 512 ◽

Cited By ~ 2

Author(s):

Sanchez-Carranza ◽

González-Maya ◽

Razo-Hernández ◽

Salas-Vidal ◽

Nolasco-Quintana ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Sesquiterpene Lactones ◽

Phase Cell ◽

Glycoprotein P ◽

Cycle Arrest ◽

P Glycoprotein ◽

M Phase ◽

Docking Calculations ◽

Hepatocellular Carcinoma Cell Line ◽

Human Hepatocellular Carcinoma Cell

Multidrug resistance (MDR) has become a major obstacle in the treatment of cancer, and is associated with mechanisms such as increased drug outflow, reduction of apoptosis, and/or altered drug metabolism. These problems can be mitigated by the coadministration of agents known as chemosensitizers, as they can reverse resistance to anticancer drugs and eventually resensitize cancer cells. We explore the chemosensitizing effect of Achillin, a guaianolide-type sesquiterpene lactone isolated from the Mexican medicinal plant Artemisia ludovisiana, to reverse MDR in Hep3B/PTX cells of hepatocellular carcinoma, which present resistance to paclitaxel (PTX). Achillin showed an important effect as chemosensitizer; indeed, the cytotoxic effect of PTX (25 nM) was enhanced, and the induction of G2/M phase cell cycle arrest and apoptosis were potentiated when combining with Achillin (100 μM). In addition, we observed that Achillin decreases P-gp levels and increases the intracellular retention of doxorubicin in Hep3B/PTX cells; in addition, homology structural modeling and molecular docking calculations predicted that Achillin interacts in two regions (M-site and R-site) of transporter drug efflux P-glycoprotein (P-gp). Our results suggest that the chemosensitizer effect demonstrated for Achillin could be associated with P-gp modulation. This work also provides useful information for the development of new therapeutic agents from guaianolide-type sesquiterpene lactones like Achillin.

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A novel 8-nitro quinoline-thiosemicarbazone analogues induces G1/S & G2/M phase cell cycle arrest and apoptosis through ROS mediated mitochondrial pathway

Bioorganic Chemistry ◽

10.1016/j.bioorg.2020.103709 ◽

2020 ◽

Vol 97 ◽

pp. 103709 ◽

Cited By ~ 4

Author(s):

Selvaraj Shyamsivappan ◽

Raju Vivek ◽

Arjunan Saravanan ◽

Thangaraj Arasakumar ◽

Thangaraj Suresh ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Mitochondrial Pathway ◽

Phase Cell ◽

Cycle Arrest ◽

M Phase

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TLC388 Induces DNA Damage and G2 Phase Cell Cycle Arrest in Human Non-Small Cell Lung Cancer Cells

Cancer Control ◽

10.1177/1073274819897975 ◽

2020 ◽

Vol 27 (1) ◽

pp. 107327481989797

Author(s):

Kun-Ming Wu ◽

Chih-Wen Chi ◽

Jerry Cheng-Yen Lai ◽

Yu-Jen Chen ◽

Yu Ru Kou

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Cyclin B1 ◽

Small Cell ◽

Phase Cell ◽

Small Cell Lung ◽

Cycle Arrest ◽

M Phase ◽

G2 Phase ◽

Induced Apoptosis

TLC388, a camptothecin-derivative targeting topoisomerase I, is a potential anticancer drug. In this study, its effect on A549 and H838 human non-small cell lung cancer (NSCLC) cells was investigated. Cell viability and proliferation were determined by thiazolyl blue tetrazolium bromide and clonogenic assays, respectively, and cell cycle analysis and detection of phosphorylated histone H3 (Ser10) were performed by flow cytometry. γ-H2AX protein; G2/M phase-associated molecules ataxia-telangiectasia mutated (ATM), CHK1, CHK2, CDC25C, CDC2, and cyclin B1; and apoptosis were assessed with immunofluorescence staining, immunoblotting, and an annexin V assay, respectively. The effect of co-treatment with CHIR124 (a checkpoint kinase 1 [CHK1] inhibitor) was also studied. TLC388 decreased the viability and proliferation of cells of both NSCLC lines in a dose-dependent manner. TLC388 inhibited the viability of NSCLC cell lines with an estimated concentration of 50% inhibition (IC50), which was 4.4 and 4.1 μM for A549 and H838 cells, respectively, after 24 hours. Moreover, it resulted in the accumulation of cells at the G2/M phase and increased γ-H2AX levels in A549 cells. Levels of the G2 phase–related molecules phosphorylated ATM, CHK1, CHK2, CDC25C, and cyclin B1 were increased in TLC388-treated cells. CHIR124 enhanced the cytotoxicity of TLC388 toward A549 and H838 cells and induced apoptosis of the former. TLC388 inhibits NSCLC cell growth by inflicting DNA damage and activating G2/M checkpoint proteins that trigger G2 phase cell cycle arrest to enable DNA repair. CHIR124 enhanced the cytotoxic effect of TLC388 and induced apoptosis.

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